Certain amino acids in the Fr98 mouse retroviral envelope were found o be essential for the brain disease induced by this virus. These amino acids were located in several separated locations in the sequence when viewed as a linear structure. In contrast when assembled as a three dimensional model based on the crystal structure of a closely related mouse retrovirus, these amino acids were located in two distinct groups. These results supported the idea that two separate but cooperative mechanisms of pathogenesis are induced by infection with this retrovirus.